Editorial

6 pages, 829 KiB

Open AccessEditorial

Plasmodium vivax Malaria and G6PD Testing

by Benedikt Ley and Lucio Luzzatto

Pathogens 2023, 12(12), 1445; https://doi.org/10.3390/pathogens12121445 - 13 Dec 2023

Viewed by 1039

Early malaria investigators were certainly correct in classifying the species falciparum and the species vivax as belonging to the same genus, Plasmodium [...] Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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Research

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17 pages, 4138 KiB

Open AccessEditor’s ChoiceArticle

Assessing the Operational Feasibility of Integrating Point-of-Care G6PD Testing into Plasmodium vivax Malaria Management in Vietnam

by Emily Gerth-Guyette, Huyen Thanh Nguyen, Spike Nowak, Nga Thu Hoang, Đặng Thị Tuyết Mai, Vũ Thị Sang, Nguyễn Đức Long, Mercy Mvundura, Nhu Nguyen, Gonzalo J. Domingo and Bùi Quang Phúc

Pathogens 2023, 12(5), 689; https://doi.org/10.3390/pathogens12050689 - 08 May 2023

Cited by 2 | Viewed by 1897

Abstract

Plasmodium vivax cases represent more than 50% of a diminishing malaria case load in Vietnam. Safe and effective radical cure strategies could support malaria elimination by 2030. This study investigated the operational feasibility of introducing point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing into malaria [...] Read more.

Plasmodium vivax cases represent more than 50% of a diminishing malaria case load in Vietnam. Safe and effective radical cure strategies could support malaria elimination by 2030. This study investigated the operational feasibility of introducing point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing into malaria case management practices. A prospective interventional study was conducted at nine district hospitals and commune health stations in Binh Phuoc and Gia Lai provinces in Vietnam over the period of October 2020 to October 2021. The STANDARD™ G6PD Test (SD Biosensor, Seoul, Republic of Korea) was incorporated to inform P. vivax case management. Case management data and patient and health care provider (HCP) perspectives, as well as detailed cost data were collected. The G6PD test results were interpreted correctly by HCP and the treatment algorithm was adhered to for the majority of patients. One HCP consistently ran the test incorrectly, which was identified during the monitoring and resulted in provision of refresher training and updating of training materials and patient retesting. There was wide acceptability of the intervention among patients and HCP albeit with opportunities to improve the counseling materials. Increasing the number of facilities to which the test was deployed and decreases in the malaria cases resulted in higher per patient cost for incorporating G6PD testing into the system. Commodity costs can be reduced by using the 10-unit kits compared to the 25 unit kits, particularly when the case loads are low. These results demonstrate intervention feasibility while also highlighting specific challenges for a country approaching malaria elimination. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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16 pages, 1766 KiB

Open AccessArticle

Glucose-6-Phosphate Dehydrogenase (G6PD) Measurement Using Biosensors by Community-Based Village Malaria Workers and Hospital Laboratory Staff in Cambodia: A Quantitative Study

by Bipin Adhikari, Rupam Tripura, Lek Dysoley, Thomas J. Peto, James J. Callery, Chhoeun Heng, Thy Vanda, Ou Simvieng, Sarah Cassidy-Seyoum, Kamala Thriemer, Arjen M. Dondorp, Benedikt Ley and Lorenz von Seidlein

Pathogens 2023, 12(3), 400; https://doi.org/10.3390/pathogens12030400 - 01 Mar 2023

Cited by 5 | Viewed by 5147

Abstract

Vivax malaria can relapse after an initial infection due to dormant liver stages of the parasite. Radical cure can prevent relapses but requires the measurement of glucose-6-phosphate dehydrogenase enzyme (G6PD) activity to identify G6PD-deficient patients at risk of drug-induced haemolysis. In the absence [...] Read more.

Vivax malaria can relapse after an initial infection due to dormant liver stages of the parasite. Radical cure can prevent relapses but requires the measurement of glucose-6-phosphate dehydrogenase enzyme (G6PD) activity to identify G6PD-deficient patients at risk of drug-induced haemolysis. In the absence of reliable G6PD testing, vivax patients are denied radical curative treatment in many places, including rural Cambodia. A novel Biosensor, ‘G6PD Standard’ (SD Biosensor, Republic of Korea; Biosensor), can measure G6PD activity at the point of care. The objectives of this study were to compare the G6PD activity readings using Biosensors by village malaria workers (VMWs) and hospital-based laboratory technicians (LTs), and to compare the G6PD deficiency categorization recommended by the Biosensor manufacturer with categories derived from a locally estimated adjusted male median (AMM) in Kravanh district, Cambodia. Participants were enrolled between 2021 and 2022 in western Cambodia. Each of the 28 VMWs and 5 LTs received a Biosensor and standardized training on its use. The G6PD activities of febrile patients identified in the community were measured by VMWs; in a subset, a second reading was done by LTs. All participants were tested for malaria by rapid diagnostic test (RDT). The adjusted male median (AMM) was calculated from all RDT-negative participants and defined as 100% G6PD activity. VMWs measured activities in 1344 participants. Of that total, 1327 (98.7%) readings were included in the analysis, and 68 of these had a positive RDT result. We calculated 100% activity as 6.4 U/gHb (interquartile range: 4.5 to 7.8); 9.9% (124/1259) of RDT-negative participants had G6PD activities below 30%, 15.2% (191/1259) had activities between 30% and 70%, and 75.0% (944/1259) had activities greater than 70%. Repeat measurements among 114 participants showed a significant correlation of G6PD readings (r_s = 0.784, p < 0.001) between VMWs and LTs. Based on the manufacturer’s recommendations, 285 participants (21.5%) had less than 30% activity; however, based on the AMM, 132 participants (10.0%) had less than 30% activity. The G6PD measurements by VMWs and LTs were similar. With the provisions of training, supervision, and monitoring, VMWs could play an important role in the management of vivax malaria, which is critical for the rapid elimination of malaria regionally. Definitions of deficiency based on the manufacturer’s recommendations and the population-specific AMM differed significantly, which may warrant revision of these recommendations. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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12 pages, 985 KiB

Open AccessArticle

Quantitative G6PD Deficiency Screening in Routine Malaria Diagnostic Units in the Brazilian Amazon (SAFEPRIM): An Operational Mixed-Methods Study

by Jose Diego Brito-Sousa, Felipe Murta, Sheila Vitor-Silva, Vanderson Sampaio, Maxwell Mendes, Brenda Souza, Talita Batista, Alicia Santos, Leonardo Marques, Laila Barbosa, Patricia Balieiro, Alexandre Silva-Neto, Renata Rabello, Marcelo Brito, Emanuelle Silva, Sheila Rodovalho, Ana Ruth Arcanjo, Gisely Melo, Judith Recht, Gonzalo J. Domingo, Suiane Valle, Rodrigo Souza, Theresa Nakagawa, Wuelton Monteiro and Marcus Lacerda Show full author list Hide full author list

Pathogens 2022, 11(11), 1328; https://doi.org/10.3390/pathogens11111328 - 11 Nov 2022

Cited by 4 | Viewed by 2183

Abstract

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency testing is not routinely performed before primaquine treatment in most Plasmodium vivax endemic areas, despite the risk of primaquine-associated hemolysis. This is due to the operational challenges associated with pragmatic G6PD testing and as such needs to be [...] Read more.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency testing is not routinely performed before primaquine treatment in most Plasmodium vivax endemic areas, despite the risk of primaquine-associated hemolysis. This is due to the operational challenges associated with pragmatic G6PD testing and as such needs to be addressed. Methods and findings: This mixed-methods operational study was aimed at implementing the quantitative point-of-care Standard^TM G6PD (SD Biosensor, Korea) screening test in malaria treatment units (MTUs) in the municipalities of Rio Preto da Eva and Mâncio Lima, in the Brazilian Amazon, between mid-January 2020 and December 2020. In total, 1286 P. vivax cases were treated based on the Standard G6PD test: 1230 had activity equal to or greater than 4.0 U/g Hb, and 56 less than 4.0 U/g Hb. No G6PD deficient (G6PDd) genotypes were found in 96 samples from the 1230, and only 21 of the 56 G6PDd cases had confirmed G6PDd genotypes. Evaluations were conducted on the proficiency of health care professionals (HCPs) training to perform the test, the reliability of testing performed in the field, and the perceptions of HCPs and patients about the implementation. Post-training proficiency was 73.4% after a 4-hour training session. This study revealed that locations with lower malaria caseloads will need regular refresher training. The test was well accepted by both HCPs and patients. Signs and symptoms of hemolysis were not always associated with malaria treatment drugs by HCPs and patients. Interpretation: Point-of-care quantitative G6PD testing can be performed at MTUs in the Brazilian Amazon to inform treatment decisions with primaquine. Limitations related to technical and cultural aspects need to be addressed further when expanding screening to larger areas. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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Review

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19 pages, 1079 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Using Serological Markers for the Surveillance of Plasmodium vivax Malaria: A Scoping Review

by Lejla Kartal, Ivo Mueller and Rhea J. Longley

Pathogens 2023, 12(6), 791; https://doi.org/10.3390/pathogens12060791 - 31 May 2023

Cited by 3 | Viewed by 3671

Abstract

The utilisation of serological surveillance methods for malaria has the potential to identify individuals exposed to Plasmodium vivax, including asymptomatic carriers. However, the application of serosurveillance varies globally, including variations in methodology and transmission context. No systematic review exists describing the advantages [...] Read more.

The utilisation of serological surveillance methods for malaria has the potential to identify individuals exposed to Plasmodium vivax, including asymptomatic carriers. However, the application of serosurveillance varies globally, including variations in methodology and transmission context. No systematic review exists describing the advantages and disadvantages of utilising serosurveillance in various settings. Collation and comparison of these results is a necessary first step to standardise and validate the use of serology for the surveillance of P. vivax in specific transmission contexts. A scoping review was performed of P. vivax serosurveillance applications globally. Ninety-four studies were found that met predefined inclusion and exclusion criteria. These studies were examined to determine the advantages and disadvantages of serosurveillance experienced in each study. If studies reported seroprevalence results, this information was also captured. Measurement of antibodies serves as a proxy by which individuals exposed to P. vivax may be indirectly identified, including those with asymptomatic infections, which may be missed by other technologies. Other thematic advantages identified included the ease and simplicity of serological assays compared to both microscopy and molecular diagnostics. Seroprevalence rates varied widely from 0–93%. Methodologies must be validated across various transmission contexts to ensure the applicability and comparability of results. Other thematic disadvantages identified included challenges with species cross-reactivity and determining changes in transmission patterns in both the short- and long-term. Serosurveillance requires further refinement to be fully realised as an actionable tool. Some work has begun in this area, but more is required. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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21 pages, 2392 KiB

Open AccessEditor’s ChoiceReview

A Review of the Current Status of G6PD Deficiency Testing to Guide Radical Cure Treatment for Vivax Malaria

by Arkasha Sadhewa, Sarah Cassidy-Seyoum, Sanjaya Acharya, Angela Devine, Ric N. Price, Muthoni Mwaura, Kamala Thriemer and Benedikt Ley

Pathogens 2023, 12(5), 650; https://doi.org/10.3390/pathogens12050650 - 27 Apr 2023

Cited by 6 | Viewed by 4305

Abstract

Plasmodium vivax malaria continues to cause a significant burden of disease in the Asia-Pacific, the Horn of Africa, and the Americas. In addition to schizontocidal treatment, the 8-aminoquinoline drugs are crucial for the complete removal of the parasite from the human host (radical [...] Read more.

Plasmodium vivax malaria continues to cause a significant burden of disease in the Asia-Pacific, the Horn of Africa, and the Americas. In addition to schizontocidal treatment, the 8-aminoquinoline drugs are crucial for the complete removal of the parasite from the human host (radical cure). While well tolerated in most recipients, 8-aminoquinolines can cause severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. G6PD deficiency is one of the most common enzymopathies worldwide; therefore, the WHO recommends routine testing to guide 8-aminoquinoline based treatment for vivax malaria whenever possible. In practice, this is not yet implemented in most malaria endemic countries. This review provides an update of the characteristics of the most used G6PD diagnostics. We describe the current state of policy and implementation of routine point-of-care G6PD testing in malaria endemic countries and highlight key knowledge gaps that hinder broader implementation. Identified challenges include optimal training of health facility staff on point-of-care diagnostics, quality control of novel G6PD diagnostics, and culturally appropriate information and communication with affected communities around G6PD deficiency and implications for treatment. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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Other

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20 pages, 1753 KiB

Open AccessCase Report

Case Series of Primaquine-Induced Haemolytic Events in Controlled Trials with G6PD Screening

by Ayleen Kosasih, Robert James, Nguyen Hoang Chau, Michelle M. Karman, Lydia Visita Panggalo, Lyndes Wini, Ngo Viet Thanh, Thomas Obadia, Ari Winasti Satyagraha, Puji Budi Setia Asih, Din Syafruddin, Walter R. J. Taylor, Ivo Mueller, Inge Sutanto, Harin Karunajeewa, Ayodhia Pitaloka Pasaribu and J. Kevin Baird

Pathogens 2023, 12(9), 1176; https://doi.org/10.3390/pathogens12091176 - 19 Sep 2023

Cited by 2 | Viewed by 1189

Abstract

Primaquine for radical cure of Plasmodium vivax malaria poses a potentially life-threatening risk of haemolysis in G6PD-deficient patients. Herein, we review five events of acute haemolytic anaemia following the administration of primaquine in four malaria trials from Indonesia, the Solomon Islands, and Vietnam. [...] Read more.

Primaquine for radical cure of Plasmodium vivax malaria poses a potentially life-threatening risk of haemolysis in G6PD-deficient patients. Herein, we review five events of acute haemolytic anaemia following the administration of primaquine in four malaria trials from Indonesia, the Solomon Islands, and Vietnam. Five males aged 9 to 48 years were improperly classified as G6PD-normal by various screening procedures and included as subjects in trials of anti-relapse therapy with daily primaquine. Routine safety monitoring by physical examination, urine inspection, and blood haemoglobin (Hb) assessment were performed in all those trials. Early signs of acute haemolysis, i.e., dark urine and haemoglobin drop >20%, occurred only after day 3 and as late as day 8 of primaquine dosing. All patients were hospitalized and fully recovered, all but one following blood transfusion rescue. Hb nadir was 4.7 to 7.9 g/dL. Hospitalization was for 1 to 7 days. Hb levels returned to baseline values 3 to 10 days after transfusion. Failed G6PD screening procedures in these trials led G6PD-deficient patients to suffer harmful exposures to primaquine. The safe application of primaquine anti-relapse therapy requires G6PD screening and anticipation of its failure with a means of prompt detection and rescue from the typically abrupt haemolytic crisis. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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18 pages, 1619 KiB

Open AccessSystematic Review

Genetic Variants of Glucose-6-Phosphate Dehydrogenase and Their Associated Enzyme Activity: A Systematic Review and Meta-Analysis

by Daniel A. Pfeffer, Ari Winasti Satyagraha, Arkasha Sadhewa, Mohammad Shafiul Alam, Germana Bancone, Yap Boum II, Marcelo Brito, Liwang Cui, Zeshuai Deng, Gonzalo J. Domingo, Yongshu He, Wasif A. Khan, Mohammad Golam Kibria, Marcus Lacerda, Didier Menard, Wuelton Monteiro, Sampa Pal, Sunil Parikh, Arantxa Roca-Feltrer, Michelle Roh, Mahmoud M. Sirdah, Duoquan Wang, Qiuying Huang, Rosalind E. Howes, Ric N. Price and Benedikt Ley Show full author list Hide full author list

Pathogens 2022, 11(9), 1045; https://doi.org/10.3390/pathogens11091045 - 14 Sep 2022

Cited by 11 | Viewed by 3826

Abstract

Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, individual patient data [...] Read more.

Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, individual patient data from studies reporting G6PD activity measured by spectrophotometry and corresponding the G6PD genotype were pooled (PROSPERO: CRD42020207448). G6PD activity was converted into percent normal activity applying study-specific definitions of 100%. In total, 4320 individuals from 17 studies across 10 countries were included, where 1738 (40.2%) had one of the 24 confirmed G6PD mutations, and 61 observations (3.5%) were identified as outliers. The median activity of the hemi-/homozygotes with A-(c.202G>A/c.376A>G) was 29.0% (range: 1.7% to 76.6%), 10.2% (range: 0.0% to 32.5%) for Mahidol, 16.9% (range 3.3% to 21.3%) for Mediterranean, 9.0% (range: 2.9% to 23.2%) for Vanua Lava, and 7.5% (range: 0.0% to 18.3%) for Viangchan. The median activity in heterozygotes was 72.1% (range: 16.4% to 127.1%) for A-(c.202G>A/c.376A>G), 54.5% (range: 0.0% to 112.8%) for Mahidol, 37.9% (range: 20.7% to 80.5%) for Mediterranean, 53.8% (range: 10.9% to 82.5%) for Vanua Lava, and 52.3% (range: 4.8% to 78.6%) for Viangchan. A total of 99.5% of hemi/homozygotes with the Mahidol mutation and 100% of those with the Mediterranean, Vanua Lava, and Viangchan mutations had <30% activity. For A-(c.202G>A/c.376A>G), 55% of hemi/homozygotes had <30% activity. The G6PD activity for each variant spanned the current classification thresholds used to define clinically relevant categories of enzymatic deficiency. Full article

(This article belongs to the Special Issue Plasmodium vivax and G6PD Deficiency: From Development of Novel Diagnostic Tools to Implementation into Routine Care)

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